Charleen T. Chu, MD, PhD
Professor of Pathology
A. Julio Martinez Chair in Neuropathology
Dr. Chu is Director of the Ophthalmic Pathology Service in the Division of Neuropathology and Co-Director of the Pathologist Investigator Residency/Research Training Program. As principal investigator, she directs a basic research program focused on mitochondrial pathobiology and Parkinson's disease, and is training faculty for the Pathology and Neuroscience Graduate programs, the MSTP and the PSTP. She is also a member of the McGowan Institute for Regenerative Medicine and the Mitochondria, Metabolism and Disease Working Group.
S701.1 Scaife Hall
3550 Terrace Street
Pittsburgh, PA 15261
Office Telephone: 412-383-5379
Clinical ExpertiseDr. Chu is director of the ophthalmic pathology service. For information on submitting specimens, visit the Eye Consults page. For information on training in academic neuropathology or ophthalmic pathology, visit the Neuropathology website.
Research InterestsDr. Chu's Lab Home Page
2010 Carnegie Science Awards Profile of Dr. Chu's Research
Cell Biology of Parkinson's Disease: Mitochondrial homeostasis, cell signaling and autophagy in neurodegeneration
Dr. Chu's research focuses on mechanisms of neurodegeneration and neuroprotection in Parkinson's and related neurodegenerative diseases. A major focus is delineating why adaptive cellular mechanisms fail to protect neurons, with emphasis on mitochondrial dysfunction, alterations in kinase signaling and autophagy. Molecular and biochemical studies in cell culture and mouse models are integrated with studies of diseased human brain tissues. We are particularly interested in potentially reversible mechanisms by which mutations in PD-linked genes affect dendritic extension/retraction and synaptic dysfunction.
Work in the Chu laboratory indicates that pathogenic mechanisms related more 5 PD models converge on dysregulation of mitochondrial kinase signaling and macroautophagy. These include the parkinsonian neurotoxins 6-OHDA, MPP+ and rotenone, and models based on mutations in PTEN-induced kinase 1 (PINK1), a mitochondrial kinase, the leucine-rich repeat kinase 2 (LRRK2), a membrane associated multidomain kinase, and ATP13A2, a lysosomal ATPase. Analysis of Parkinson disease and Lewy body dementia brain tissues reveal similar alterations in the subcellular localization of phosphorylated kinases and transcription factors, often in association with "mitophagosomes," in susceptible neurons early in the disease process. In addition, we have found that oxidative stress reduces microtubule dynamics through effects on SIRT2 function. Thus, we will examine the contributions of both mitophagy and altered mitochondrial transport in parkinsonian dendrite degeneration.
Kinases that are activated in toxin (ERK1/2) or genetic (LRRK2) models of Parkinson disease appear to promote mitophagy while suppressing mitochondrial biogenesis. The resulting "mitophagic stress" results in inadequate mitochondrial densities in the dendrites, and this loss of mitochondria precedes dendrite retraction. ERK1/2 directly phosphorylates the mitochondrial transcription factor A to reduce its function in mtDNA transcription, and we are characterizing the functional effects of other phosphorylation sites we have identified. Mutant LRRK2 dysregulates mitochondrial calcium handling, leading to increased mitophagy and dendrite retraction. Interestingly, these effects are opposed by PINK1, and current efforts are aimed at delineating whether or not mitochondrial calcium and nucleotide transporter functions are targeted by these kinases.
We have recently identified a phospholipid signal by which mitochondria signal to the autophagy machinery to mediate the selective removal of damaged mitochondria in response to 6-OHDA and complex I inhibition. There is an enzyme-dependent redistribution of cardiolipin from the inner mitochondrial membrane to the outer surface of mitochondria, and cardiolipin thus exposed is bound directly by the autophagy protein LC3. Current efforts are directed at determining the potential role of PINK1 in regulating cardiolipin-mediated mitophagy. Given that PINK1 shows such strong neuroprotective functions, we are also studying mechanisms that regulate its stability and degradation.
TechniquesProtein biochemistry, molecular cell biology, mass spectrometry and phospho-proteomics, quantitative RT-PCR, immunochemistry, multi-label confocal microscopy, electron microscopy, stereotactic brain injections, RNA interference.
Dr. Chu is a member of the Graduate Programs of Cellular and Molecular Pathology (CMP) and Center for Neuroscience (CNUP), the Medical Scientist Training Program (MSTP) and the Physician Scientist Training Program (PSTP). She is committed to career development of pre-doctoral, post-doctoral and physician-scientist trainees, developing and directing for 10 years a MSTP Professional Development course focused on grant writing and peer-review, which is now emulated by other MSTP and graduate programs nationwide. She is founding co-director for the Pathologist Investigator Residency/Research Training Program. This "PI-training track" is designed to develop the next generation of physician-scientist leaders, independently-funded Academic Pathologists pursuing combined research and diagnostic careers.
NIH ResearchView Dr. Chu's NIH RePORT on nih.gov
Selected PublicationsView Dr. Chu's recent publications on PubMed
View Dr. Chu's previous publications on PubMed
- JE Knickelbein, J Kovarik, DK Dhaliwal & CT Chu. (2013) Acanthamoeba keratitis: A clinico-pathologic case report and review of the literature. Human Pathol, 44: 918-922.
- SJ Cherra III, E Steer, AM Gusdon, K Kiselyov & CT Chu. (2013) Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons. Am J Pathol, 182: 474-484. PMCID: PMCID: PMC3562730
- CT Chu, J Ji, RK Dagda, JF Jiang, YY Tyurina, AA Kapralov, VA Tyurin, N Yanamala, IH Shrivastava, D Mohammadyani, KZQ Wang, J Zhu, J Klein-Seetharaman, K Balasubramanian, AA Amoscato, G Borisenko, Z Huang, AM Gusdon, A Cheikhi, EK Steer, R Wang, C Baty, S Watkins, I Bahar, H Bayır & VE Kagan (2013) Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nature Cell Biol 15:1197-1205. doi: 10.1038/ncb2837. PMCID: PMC3806088. Featured in Science magazine's Editors' Choice, 25 Oct 2013 (Science 342: 403, 2013)
- F1000 Recommended: Nektarios Tavernarakis & Vassiliki Nikoletopoulou: F1000 Cell Biology, 28 Oct 2013; Zu-Hang Sheng & Rajat Puri: F1000 Neuroscience, 06 Dec 2013; Tamotsu Yoshimori & Junya Hasegawa: F1000 Cell Biology, 12 Dec 2013; Heinz Osiewacz: F1000 Microbiology, 19 Dec 2013; Daniel Klionsky: F1000 Cell Biology, 20 Jan 2014. Available at http://f1000.com/prime/718109987
- CK Pride, L Mo, K Quesnelle, RK Dagda, D Murillo, L Geary, C Corey, R Portella, S Zharikov, C St Croix, S Maniar, CT Chu, N Khoo & S Shiva (2014) Nitrite activates protein kinase A in normoxia to mediate mitochondrial fusion and tolerance to ischemia reperfusion. Cardiovascular Res, 101: 57-68. doi: 10.1093/cvr/cvt224. PMCID: PMC3868348
- RK Dagda, I Pien, R Wang, J Zhu, KZQ Wang, J Callio, TD Banerjee, RY Dagda & CT Chu (2014) Beyond the mitochondrion: cytosolic PINK1 remodels dendrites through Protein Kinase A. J Neurochem 128: 864-877. doi: 10.1111/jnc.12494. PMCID: PMC3951661.
- Commentary: doi: 10.1111/jnc.12529. J Neurochem 128: 787-789.
- BB Chen, TA Coon, JR Glasser, C Zou, B Ellis, T Das, AC McKelvey, S Rajbhandari, T Lear, C Kamga, S Shiva, CJ Li, JM Pilewski, J Callio, CT Chu, A Ray, P Ray, YY Tyurina, VE Kagan, and RK Mallampalli. (2014) E3 ligase subunit Fbxo15 and PINK1 kinase regulate cardiolipin synthase 1 stability and mitochondrial function in pneumonia. Cell Reports 7: 476-487. doi: 10.1016/j.celrep.2014.02.048. NIHMSID #576085
- KZQ Wang, J Zhu, RK Dagda, G Uechi, SJ Cherra III, AM Gusdon, M Balasubramani & CT Chu. (2014) ERK-mediated phosphorylation of TFAM downregulates mitochondrial transcription. Mitochondrion, in press. doi: 10.1016/j.mito.2014.04.008. NIHMSID #587439
- VP Patel & CT Chu. (2014) Decreased SIRT2 activity leads to altered microtubule dynamics in oxidatively-stressed neuronal cells: Implications for Parkinson's disease. Exp. Neurol., in press. doi: 10.1016/j.expneurol.2014.04.024.
- E Plowey, JW Johnson, D Eisenberg, NM Valentino, YJ Liu & CT Chu. (2014) Mutant LRRK2 overexpression in cultured cortical neurons elicits glutamatergic synapse activity and excitotoxic neurite degeneration. Biochim. Biophys. Acta (Molecular Basis of Disease) 1842: 1596-1603. Available at http://www.sciencedirect.com/science/article/pii/S0925443914001446. PMCID: PMC4144018.
- LH Sanders, J McCoy, X Hu, PG Mastroberardino, BC Dickinson, CJ Chang, CT Chu, B Van Houten, JT Greenamyre. (2014) Mitochondrial DNA damage: molecular marker of vulnerable nigral neurons in Parkinson's disease. Neurobiol Dis 70: 214-223. PMCID: PMC4144978.
- A Nuschke, M Rodrigues, DB Stolz, CT Chu, L Griffith & A Wells. (2014) Human mesenchymal stem cells/multipotent stromal cells consume accumulated autophagosomes early in differentiation. Stem Cell Res Ther 5: 140 (14 pages) PMID: 25523618
- NK Mesiwala, CT Chu, LV Raju. (2014) Infectious crystalline keratopathy predominantly affecting the posterior cornea. Int J Clin Pathol 7: 5250-5253. PMCID: PMC4152095
- M Bueno, M Mosher, C Kamga, C Corey, D Stolz, C StCroix, M Rojas, S Shiva, CT Chu & AL Mora. (2015) PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. J Clin Invest 125: 521-538. PMCID: PMC4319413
- AM Gusdon, F Fang, J Chen, CE Mathews, W Li, CT Chu, JQ Ding & SD Chen (2015) Association of the mt-ND2 5178A/C polymorphism with Parkinson's disease. Neurosci Lett 587: 98-101. PMID: 25511548
- AK Au, Y Chen, L Du, CM Smith, MD Manole, SA Baltagi, CT Chu, RK Aneja, H Bayir, PM Kochanek & RSB Clark. Ischemia-induced autophagy contributes to neurodegeneration in cerebellar Purkinje cells in the developing brain and in primary cortical neurons in vitro. Biochim. Biophys. Acta (Molecular Basis of Disease), In press. doi: 10.1016/j.bbadis.2015.06.007
Selected Books, Reviews, and Clinical AritclesZ Yue & CT Chu, Editors. (2012) Autophagy of the Nervous System: Cellular Self-Digestion in Neurons and Neurological Diseases. World Scientific Press, Singapore, 2012. 440 pp. ISBN - 978-981-4350-44-0. Available at World Scientific and Amazon.
E Oczypok, TD Oury & CT Chu. (2013) It's a cell eat cell world: Autophagy and phagocytosis. Am J Pathol 182: 612-622.
JE Knickelbein, J Kovarik, DK Dhaliwal & CT Chu. (2013) Acanthamoeba keratitis: A clinico-pathologic case report and review of the literature. Human Pathol, 44: 918-922.
J Zhu, KZQ Wang & CT Chu. (2013) After the banquet: Mitochondrial biogenesis, mitophagy and cell survival. Autophagy 9: 1663-76.
M Verma, EK Steer & CT Chu. (2013) ERKed by LRRK2: A cell biological perspective on hereditary and sporadic Parkinson's disease. Biochim Biophys Acta (Molecular Basis of Disease) In press.